Periodontal tissue destruction involves the elicitation of a host-response by oral pathogens capable of invading the connective tissue. A prominent bacterium in periodontal infections is P. gingivalis, which produces two well defined virulence factors, LPS and fimbriae. Individuals with diabetes are at a higher risk for periodontal disease than non-diabetics. The goal of this project is to investigate mechanisms which might contribute to an enhanced risk of periodontal infection in non- insulin-dependent diabetics (NIDDM). NIDDM is a polygenic disorder that involves resistance to insulin action and occurs most frequently in conjunction with obesity. Individuals with NIDDM and murine models of NIDDM exhibit alterations in cytokine expression, particularly over-expression of TNF-alpha. A breakthrough in understanding the mechanisms leading to NIDDM occurred with the discovery that obese mice which develop NIDDM have mutations in the gene encoding leptin (ob/ob mice). These mice over-express the cytokine TNF and have defects in insulin receptor signaling. Humans with NIDDM also exhibit similar defects in TNF expression and insulin receptor signaling. The goal of this project is to determine whether dysregulation of TNF in NIDDM alters the host-response rendering these individuals more susceptible to periodontal pathogens. We will examine the response of ob/ob diabetic mice to P. gingivalis LPS and P. gingivalis fimbriae and directly test the impact of TNF hyper- expression in ob/ob mice by inhibiting TNF activity and measuring the consequences.